ArticleLiterature Review

Antifungal Prophylaxis and Pre-Emptive Therapy

Authors:
  • Università degli Studi di Genova and IRCCS San Martino-IST, Genova, Italy
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Abstract

In recent years, several reports have underlined the increasing role of fungal infections as a cause of morbidity and mortality in hospitalized non-haematological patients. For this reason, and also in light of the high mortality rate associated with these infections, chemoprophylaxis has been advocated for surgical patients hospitalized in intensive care units (ICUs). The available evidence suggests that the triazoles fluconazole and itraconazole are able to decrease Candida colonization and possibly infection compared with placebo, but this result has only been obtained in high-risk patients undergoing repeated surgical procedures for tertiary peritonitis. Consequently, triazole antifungal prophylaxis should be used with caution, and only in patients at high risk of invasive candidiasis, including high-risk surgical and ICU patients. A pre-emptive approach, defined as initiating antifungal treatment without confirmation of fungal infection, seems to be effective and safe.

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... Routine fluconazole prophylaxis in the ICU may be associated with a significant increase in non-albicans, azole-resistant fungaemia, and should therefore be considered carefully; antifungal prophylaxis may also result in avoidable drug-related toxicity [3,42]. Some authors recommend that triazole prophylaxis for the prevention of invasive Candida infections should be reserved only for particularly high-risk ICU populations, such as patients undergoing repeated abdominal surgery for tertiary peritonitis and/or acute pancreatitis [43]. Pre-emptive therapy, i.e. early initiation of treatment before C/IC has been diagnosed with certainty, may thus be a more appropriate alternative to chemoprophylaxis, especially when combined with infection control measures [13,42,43]. ...
... Some authors recommend that triazole prophylaxis for the prevention of invasive Candida infections should be reserved only for particularly high-risk ICU populations, such as patients undergoing repeated abdominal surgery for tertiary peritonitis and/or acute pancreatitis [43]. Pre-emptive therapy, i.e. early initiation of treatment before C/IC has been diagnosed with certainty, may thus be a more appropriate alternative to chemoprophylaxis, especially when combined with infection control measures [13,42,43]. Pre-emptive therapy is based on a combination of risk factor evaluations and assessment of diagnostic markers (e.g. ...
... Pre-emptive therapy is based on a combination of risk factor evaluations and assessment of diagnostic markers (e.g. Candida colonization, b-D-glucan, procalcitonin, fungal DNA, mannan/anti-mannan antibodies, and Candida germ-tube antibodies) [44][45][46], and as such, encompasses a variety of different strategies aimed at selecting patients suitable for early treatment [41][42][43]47]. For example, a 'Candida score' integrating the presence of risk factors and the extent of Candida colonization has been shown to be a good predictor of IC [45]. ...
Article
Clin Microbiol Infect 2011; 17 (Suppl. 1): 1–12 Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide, with a particularly strong impact and high incidence in the intensive-care unit, where there is a need for new treatment options and strategies. The echinocandin anidulafungin has broad in vitro activity against a wide range of Candida species, along with favourable pharmacokinetics that allow administration in hepatic and renal impairment and with any comedication without the need for dose adjustments. The efficacy and safety of anidulafungin for the treatment of C/IC were demonstrated in a number of clinical studies and by some limited data from clinical practice. In a randomized comparative trial for the treatment of C/IC in adults, 76% of patients receiving anidulafungin and 60% of those given fluconazole were treated successfully (95% CI for difference: 4–27; p 0.01). Post hoc analyses suggest that anidulafungin is significantly more effective than standard-dose fluconazole for the treatment of candidaemia in critically ill patients. Anidulafungin is generally well tolerated, with commonly reported side effects including headache, hypokalaemia, gastrointestinal symptoms, abnormal liver function test results, and rash. In pharmaco-economic analyses, anidulafungin compared favourably with fluconazole (in terms of overall costs and hospital resource use) as well as with other echinocandins. Echinocandins, including anidulafungin, are now generally recommended as first-line therapy in moderately to severely ill patients, those with prior azole exposure, and patients with C/IC caused by Candida glabrata or Candida krusei.
... Prophylaxis was defined as the administration of fluconazole in the presence of risk factors for invasive candidiasis without clinical signs and symptoms of infection [13]. Pre-emptive treatment was defined as the administration of fluconazole with evidence of significant Candida colonization without the proof of invasive fungal infection [8,14]. ...
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Objectives: The study aims to assess the population pharmacokinetics of fluconazole and the adequacy of current dosages and breakpoints against Candida albicans and non-albicans spp. in liver transplant (LT) patients. Patients and methods: Patients initiated i.v. fluconazole within 1 month from liver transplantation (LTx) for prevention or treatment of Candida spp. infections. Multiple assessments of trough and peak plasma concentrations of fluconazole were undertaken in each patient by means of therapeutic drug monitoring. Monte Carlo simulations were performed to define the probability of target attainment (PTA) with a loading dose (LD) of 400, 600, and 800 mg at day 1, 7, 14, and 28 from LTx, followed by a maintenance dose (MD) of 100, 200, and 300 mg daily of the pharmacokinetic/pharmacodynamic target of AUC24h/MIC ratio ≥ 55.2. Results: Nineteen patients were recruited. A two-compartment model with first-order intravenous input and first-order elimination was developed. Patient's age and time elapsed from LTx were the covariates included in the final model. At an MIC of 2 mg/L, a LD of 600 mg was required for optimal PTAs between days 1 and 20 from LTx, while 400 mg was sufficient from days 21 on. A MD of 200 mg was required for patients aged 40-49 years old, while a dose of 100 mg was sufficient for patients aged ≥ 50 years. Conclusions: Fluconazole dosages of 100-200 mg daily may ensure optimal PTA against C. albicans, C. parapsilosis, and C. tropicalis. Higher dosages are required against C. glabrata. Estimated creatinine clearance is not a reliable predictor of fluconazole clearance in LT patients.
... Surgical site infections (SSI) are the third most frequently reported nosocomial infection in hospitalized patients [8], and an increasing number of SSIs are attributable to fungi [9], in particular Candida albicans [8,9]. Compared to patients with suspicion of IFI, an overtreatment is less acceptable in patients with SSI [10,11]. ...
Article
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Background Broad-range fungal inter spacer region (ITS) polymerase chain reaction (PCR) has been evaluated for the detection and identification of fungi in clinical specimens from severely immunocompromised patients, but not in non-selected patients. Thus, the aim of this study was to compare the diagnostic performance of ITS PCR with that of fungal culture and to investigate its clinical impact on the diagnosis of fungal infections in non-immunocompromised patients. The corresponding patients’ data were retrieved by detailed medical chart reviews. Results Results from 251 specimens showed a high concordance of 89.6 % for ITS PCR and fungal culture. The analytical sensitivity and specificity of ITS PCR considering culture as gold standard were 87.7 and 90.3 %, respectively, the positive and negative predictive value (PPV and NPV) were 76 and 95.5 %, respectively. Assessing the clinical probability of a fungal infection based on detailed chart reviews, PCR had a clinical sensitivity of 88.9 %, a specificity of 86.3 %, a PPV of 64.0 % and a NPV of 96.6 %. The overall performance of fungal broad-range PCR was similar to that of culture. Conclusions Our data show that, in non-selected and non-immunocompromised patients, the performance of ITS PCR is similar to that of culture for detecting fungal infections, not the least because sensitivity of culture in patients under antifungal treatment is surprisingly high. Compared to culture, PCR has the advantage of a rapid time-to-result (approximately two working days), proper identification of rare pathogens, prompt initiation of a species-targeted antifungal treatment, and prospects for automation. Electronic supplementary material The online version of this article (doi:10.1186/s12866-016-0752-1) contains supplementary material, which is available to authorized users.
... The antifungal agent itraconazole (ITCZ) is used as a therapeutic or preventive drug for superficial mycosis, including candidiasis and trichophytia [7][8][9], and is often administered to CTD patients. Since ITCZ potently inhibits the activity of P450 (CYP) 3A and P-glycoprotein, which is encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) [10][11][12][13], the blood concentration of tacrolimus, which is metabolized by CYP3A and transported by ABCB1, increases following ITCZ administration [14][15][16]. ...
Article
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The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD). Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state. The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = -0.482, P = 0.009). In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.
... Prophylaxis [42] Wound should be nursed clean and dry and be allowed to drain completely. Moreover, long-term compression dressing should be avoided. ...
Article
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Invasive fungal infection is one of the major complication of severe burns which can induce local or systemic inflammatory response and cause serious substantial damage to the patient. The incidence of fungal infection for burn victims is increasing dramatically during recent years. This guideline, organized by Chinese Society of Burn Surgeons, aims to standardize the diagnosis, prevention and treatment of burn invasive fungal infection. It can be used as one of the tools for treatment of major burn patients.
... En adultos el uso de profilaxis con fluconazol en los pacientes críticos con alto riesgo de candidiasis invasiva reduce su incidencia pero no parece influir en 71 . No está recomendada en toda la población de los pacientes críticos y se reserva para pacientes de riesgo, como aquellos sometidos a cirugía abdominal de repetición por peritonitis terciaria y/o pancreatitis aguda 72 . Las guías IDSA 39 recomiendan la profilaxis con fluconazol a 6 mg/kg/día en aquellos pacientes adultos ingresados en unidades de cuidados intensivos con alto riesgo de candidiasis invasiva con un grado de evidencia B-I. ...
Article
Candida yeasts are ubiquitous commensals, which can cause opportunistic infection in any location of the body. The source of infection may be both endogenous and exogenous. Invasive candidiasis encompasses different entities ranging from invasive candidiasis to disseminated multiorgan infection. Invasive candidiasis is the third leading cause of nosocomial bloodstream infection and the fourth of all nosocomial infections. It is also the most common invasive fungal infection in non-neutropenic critically ill patients, with a remarkable increase in the last 20 years owing to the increased survival of these patients and to more complex diagnostic, therapeutic and surgical procedures. Its incidence in infants, according to recent reviews, stands at 38.8 cases/100,000 children younger than 1 year. Candida albicans remains the most frequent isolate in invasive infections, although infections caused by other species have risen in the last years, such as C. kruzsei, C. glabrata and C. parapsilosis; the latter causing invasive candidiasis mainly associated with central venous catheter management, especially in neonatal units. The overall mortality of invasive candidiasis is high, with 30-day mortality reaching 20-44% in some series involving paediatric patients. This report provides an update on incidence, epidemiology, clinical presentation, diagnosis, treatment and outcome of invasive infection by Candida spp. in the paediatric patient. Copyright © 2010 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.
... Although it is outside the scope of this article to critically review all of the studies examining prophylaxis and preventative strategies for IC in the ICU, there are many studies and reviews on this topic. [185][186][187][188][189][190][191] Identification of a sufficiently high-risk group or incidence has been an issue for most studies. A few meta-analyses have suggested potential mortality benefits with fluconazole prophylaxis; however, with an incidence of 1% to 2% in most ICU populations, more than 200 patients would need to undergo prophylaxis to prevent 1 infection. ...
Article
Invasive fungal infections (IFI) and fungal sepsis in the intensive care unit are increasing and are associated with considerable morbidity and mortality. In this setting, IFI are predominantly caused by Candida species. Outcomes continue to be suboptimal; however, there are a few key clinician modifiable factors. PK-PD studies with the approved antifungal agents have provided guidance on the dosing strategy that predicts improved outcome. In addition, time to therapy is a critical element. Therefore early recognition through improved risk factor analysis and diagnostics will be key developments. Source control for infected devices and endophthalmitis must be considered.
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El conocimiento, diagnóstico, manejo y pronóstico de la Enfermedad Fúngica Invasora (EFI) en los pacientes inmunodeprimidos o con enfermedades de base, sigue siendo un tema complejo de abordar. En los últimos años, debido a los avances médicos y el uso de técnicas novedosas cada vez más invasivas y tratamientos cada vez más inmunosupresores, se ha incrementado de una manera notable, el número de enfermos susceptibles con factores de riesgo para contraer infecciones oportunistas potencialmente mortales que, ante el alto nivel de sospecha, deben diagnosticarse de una manera oportuna y tratarse eficaz y rápidamente. Cada día, se amplía el número de patógenos fúngicos asociados a este tipo de patología infecciosa, tanto de hongos ya conocidos (como Candida, Cryptococcus, Aspergillus y Mucor), como de nuevos hongos emergentes, muchos de ellos más virulentos y frecuentemente asociados a resistencia antifúngica o al fracaso de las pautas terapéuticas disponibles. Por todo ello, es muy importante la actualización y adaptación del conocimiento científico sobre esta realidad cada vez más presente en el quehacer diario de la práctica médica. El presente proyecto editorial tiene como principal objetivo proporcionar una herramienta clara, actual y concisa para la atención integral de las poblaciones con riesgo de EFI por parte del personal sanitario en el campo de la enfermedad infecciosa. Esta obra especializada, de presentación agradable y lectura sencilla, pretende facilitar la aproximación clínico-diagnóstica de la EFI incluyendo el enfoque profiláctico y terapéutico más adecuado para cada escenario. Todos los aspectos de la EFI (generalidades, incidencia, evaluación del riesgo, detección y diagnóstico, fármacos antifúngicos, pautas de tratamiento, seguimiento y pronóstico), son abordados en diez secciones tipo separatas de entrega mensual. La redacción de cada separata ha sido realizada por expertos en el tema abordado y más allá de los conocimientos teórico-prácticos o las dificultades inherentes al tema, se ha tenido un interés especial en resaltar la experiencia personal de los autores incluyendo ayudas visuales así como tablas de manejo y seguimiento para facilitar la comprensión del área temática. Para la redacción de cada una de las separatas, cada autor contó siempre con el apoyo, consenso y aporte académico de los demás autores en todos los aspectos relacionados a la ejecución de cada una de las secciones.
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To assess risk factors for development of candidal blood stream infections (CBSIs), a prospective cohort study was performed at 6 sites that involved all patients admitted to the surgical intensive care unit (SICU) for >48 h over a 2-year period. Among 4276 such patients, 42 CBSIs occurred (9.82 CBSIs per 1000 admissions). The overall incidence was 0.98 CBSIs per 1000 patient days and 1.42 per 1000 SICU days with a central venous catheter in place. In multivariate analysis, factors independently associated with increased risk of CBSI included prior surgery (relative risk [RR], 7.3), acute renal failure (RR, 4.2), receipt of parenteral nutrition (RR, 3.6), and, for patients who had undergone surgery, presence of a triple lumen catheter (RR, 5.4). Receipt of an antifungal agent was associated with decreased risk (RR, 0.3). Prospective clinical studies are needed to identify which antifungal agents are most protective and which high-risk patients will benefit from antifungal prophylaxis.
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Infections caused by Candida spp. are a major cause of morbidity and mortality in critically ill patients and usually develop from endogenous colonization. We assessed the effectiveness of adding fluconazole to a selective digestive decontamination regimen to prevent candidal infections. We performed a prospective, randomized, double-blind, placebo-controlled trial among medical and surgical intensive care unit patients at a large university hospital. All adult patients mechanically ventilated for at least 48 h with an expectation to remain so for at least an additional 72 h, and receiving selective decontamination of the digestive tract. Patients were randomly assigned fluconazole 100 mg daily (n=103) or placebo (n=101). Candida infections occurred less frequently in the fluconazole group (5.8%) than in the placebo group (16%; rate ratio 0.35; Cl(95) 0.11-0.94). Some 90% of candidemia episodes occurred in the placebo group (rate ratio for fluconazole use 0.10; Cl(95) 0.02-0.74). The rate of treatment failure, development of candidal infection, or increased colonization, was 32% in the fluconazole group and 67% in the placebo group (P<0.001). Crude in-hospital mortality was similar in the two groups (39% fluconazole vs. 41% placebo). Prophylactic use of fluconazole in a selected group of mechanically ventilated patients at high risk for infection reduces the incidence of Candida infections, in particular candidemia.
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To evaluate the impact of fluconazole prophylaxis on the incidence of fungal infections and on mortality among critically ill surgical patients. Meta-analysis of randomized, placebo-controlled trials of fluconazole prophylaxis. Subjects participating in the clinical trials in this area. We identified four randomized studies comparing fluconazole to placebo for prevention of fungal infections in the surgical intensive care unit (SICU). The studies enrolled 626 patients and used differing dosing regimens of fluconazole. All trials were double-blind and two were multicenter studies. Fluconazole administration significantly reduced the incidence of fungal infections (pooled odds ratio, 0.44; 95% confidence interval, 0.27-0.72; p < .001). However, fluconazole prophylaxis was not associated with a survival advantage (pooled OR for mortality, 0.87; 95% confidence interval, 0.59-1.28; p = NS). Fluconazole did not statistically alter the rate of candidemia, as this was low across the studies and developed in only 2.2% of all participants. Performing a sensitivity analysis and including two additional studies that indirectly examined fluconazole prophylaxis in the critically ill did not change our observations. Data from the reports reviewed were insufficient to allow comment on the impact of fluconazole prophylaxis on resource utilization, the distribution of non-albicans species of Candida, and the emergence of antifungal resistance. Generally, fluconazole appeared to be safe for SICU patients. Prophylactic fluconazole administration for prevention of mycoses in SICU patients appears to successfully decrease the rate of these infections, but this strategy does not improve survival. The absence of a survival advantage may reflect the few studies in this area and the possibility that this issue has not been adequately studied. Because of the potential for both resistance and emergence of non-albicans isolates, clinicians must consider these issues when evaluating fluconazole prophylaxis in the SICU. Future trials should focus on more precisely identifying patients at high risk for fungal infections and on determining if broader use of fluconazole alters the distribution of candidal species seen in the SICU and impacts measures of resource utilization such as length of stay and duration of mechanical ventilation.
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To determine whether systemic antifungal prophylaxis decreases infectious morbidity and mortality in nonneutropenic, critically ill, trauma and surgical intensive care unit (ICU) adult patients. Systematic review and meta-analysis of randomized clinical trials. We used a fixed effect model, with risk ratio (RR) and 95% confidence intervals (CI). Patients admitted to ICU after surgery or trauma, with multiple risk factors for fungal infections. Nine studies (seven double blind) with a total of 1,226 patients compared ketoconazole (three) or fluconazole (six) to placebo (eight) or no treatment (one). Prophylaxis with azole was associated with reduced rates of candidemia (RR 0.30, 95% CI 0.10-0.82), mortality attributable to Candida infection (RR 0.25, 95% CI 0.08-0.80), and overall mortality (RR 0.60, 95% CI 0.45-0.81). Time to event analysis showed a significantly lower probability of fungal infections in treated patients. There was no evidence of statistical heterogeneity between studies, and publication bias assessment gave a negative results. There was, however, wide variability in the definition and reporting of some relevant clinical outcomes (e.g., confirmed or suspected infections, colonization) and pooling of these outcome measures was not feasible. Prophylaxis of candidal infection among critically ill ICU patients has beneficial effect on certain outcome measures, but additional data from well designed clinical trials and long-term epidemiological observations are needed to provide firm recommendations for the selection of subgroups of patients who would most benefit from prophylaxis and to determine the effect of prophylaxis on fungal resistance patterns.
Article
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Infection represents a frequent complication among patients in Intensive Care Units (ICUs) and mortality is high. In particular, the incidence of fungal infections, especially due to Candida spp., has been increasing during the last years. In a retrospective study we studied the etiology of candidemia in critically ill patients over a five-year period (1999-2003) in the ICU of the San Martino University Hospital in Genoa, Italy. In total, 182 episodes of candidaemia were identified, with an average incidence of 2.22 episodes/10,000 patient-days/year (range 1.25-3.06 episodes). Incidence of candidemia increased during the study period from 1.25 in 1999 to 3.06/10,000 patient-days/year in 2003. Overall, 40% of the fungemia episodes (74/182) were due to C.albicans, followed by C. parapsilosis (23%), C.glabrata (15%), C.tropicalis (9%) and other species (13%). Candidemia due to non-albicans species increased and this was apparently correlated with an increasing use of azoles for prophylaxis or empirical treatment. The study demonstrates a shift in the species of Candida causing fungemia in a medical and surgical ICU population during a 5 year period. The knowledge of the local epidemiological trends in Candida species isolated in blood cultures is important to guide therapeutic choices.
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To obtain a score for deciding early antifungal treatment when candidal infection is suspected in nonneutropenic critically ill patients. Analysis of data collected from the database of the EPCAN project, an ongoing prospective, cohort, observational, multicenter surveillance study of fungal infection and colonization in intensive care unit (ICU) patients. Seventy-three medical-surgical ICUs of 70 teaching hospitals in Spain. A total of 1,699 ICU patients aged 18 yrs and older admitted for at least 7 days between May 1998 and January 1999 were studied. Surveillance cultures of urine, tracheal, and gastric samples were obtained weekly. Patients were grouped as follows: neither colonized nor infected (n=719), unifocal or multifocal Candida colonization (n=883), and proven candidal infection (n=97). The odds ratio (OR) for each risk factor associated with colonization vs. proven candidal infection was estimated. A logistic regression model was performed to adjust for possible confounders. The "Candida score" was obtained according to the logit method. The discriminatory power was evaluated by the area under the receiver operating characteristics curve. In the logit model, surgery (OR=2.71, 95% confidence interval [CI], 1.45-5.06); multifocal colonization (OR=3.04, 95% CI, 1.45-6.39); total parenteral nutrition (OR=2.48, 95% CI, 1.16-5.31); and severe sepsis (OR=7.68, 95% CI, 4.14-14.22) were predictors of proven candidal infection. The "Candida score" for a cut-off value of 2.5 (sensitivity 81%, specificity 74%) was as follows: parenteral nutrition, +0.908; surgery, +0.997; multifocal colonization, +1.112; and severe sepsis, +2.038. Central venous catheters were not a significant risk factor for proven candidal infection (p=.292). In a large cohort of nonneutropenic critically ill patients in whom Candida colonization was prospectively assessed, a "Candida score">2.5 accurately selected patients who would benefit from early antifungal treatment.
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Invasive candida infections are a major cause of morbidity and mortality in preterm infants. We performed a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of fungal colonization and infection in very-low-birth-weight neonates. During a 15-month period, all neonates weighing less than 1500 g at birth from eight tertiary Italian neonatal intensive care units (322 infants) were randomly assigned to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). We performed weekly surveillance cultures and systematic fungal susceptibility testing. Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P<0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P=0.005 for the 6-mg group and P=0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect. Prophylactic fluconazole reduces the incidence of colonization and invasive candida infection in neonates weighing less than 1500 g at birth. The benefit of treating candida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869 [controlled-trials.com]).
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Invasive aspergillosis (IA) is an important cause of mortality in patients with hematologic malignancies. However, IA appears to be gaining a foothold in the intensive care unit (ICU) in patients without classical risk factors. A recent study described 89 cases of IA in patients in a medical ICU without leukemia or cancer. The diagnosis of IA remains difficult and is often established too late. Galactomannan (GM) is an exo-antigen released from Aspergillus hyphae while they invade host tissue. This prospective single-center study was conducted to investigate the role of GM in bronchoalveolar lavage (BAL) fluid as a tool for early diagnosis of IA in the ICU. All patients with risk factors identified in our earlier study were evaluated. BAL for culture and GM detection, serum GM levels, and computed tomography scan were obtained for all included patients with signs of pneumonia. Patients were classified as having proven, probable, or possible IA. A total of 110 patients out of 1,109 admissions were eligible. There were 26 proven IA cases. Using a cutoff index of 0.5, the sensitivity and specificity of GM detection in BAL fluid was 88 and 87%, respectively. The sensitivity of serum GM was only 42%. In 11 of 26 proven cases, BAL culture and serum GM remained negative, whereas GM in BAL was positive. IA is common in immunocompromised, critically ill patients. GM detection in BAL fluid seems to be useful in establishing or excluding the diagnosis of IA in the ICU.
Article
• We reviewed the clinical courses of 63 surgical patients who had experienced one or more days of fungemia, to determine the clinical setting for such infections and to define indications for systemic therapy. Fifty-one patients experienced fungemia as a late complication of intraperitoneal infection. Candida was identified as part of a polymicrobial flora in 70%. If untreated, the mortality was 83% (30 of 36). No untreated patients with fungemia for more than one day survived. Adequate therapy with amphotericin B (total dose, >3 mg/kg) improved survival to 67% (ten of 15). Autopsies performed in 20 cases revealed visceral Candida microabscesses in seven, with the gastrointestinal tract (12) and intra-abdominal abscess (five) as the most common sources of fungi. These data support the concept of Candida as an important participant in polymicrobial infection and recommend therapy with amphotericin B for patients with intraperitoneal infection experiencing fungemia.(Arch Surg 1982;117:1272-1275)
Article
Background. Candida species are important nosocomial pathogens in neonatal intensive care unit (NICU) patients. Methods. A prospective cohort study was performed in six geographically diverse NICUs from 1993 to 1995 to determine the incidence of and risk factors for candidemia, including the role of gastrointestinal (GI) tract colonization. Study procedures included rectal swabs to detect fungal colonization and active surveillance to identify risk factors for candidemia. Candida strains obtained from the GI tract and blood were analyzed by pulsed field gel electrophoresis to determine whether colonizing strains caused candidemia. Results. In all, 2847 infants were enrolled and 35 (1.2%) developed candidemia (12.3 cases per 1000 patient discharges or 0.63 case per 1000 catheter days) including 23 of 421 (5.5%) babies ≤1000 g. After adjusting for birth weight and abdominal surgery, forward multivariate logistic regression analysis demonstrated significant risk factors, including gestational age <32 weeks, 5-min Apgar <5; shock, disseminated intravascular coagulopathy, prior use of intralipid, parenteral nutrition, central venous catheters, H2 blockers, intubation or length of stay >7 days before candidemia (P < 0.05). Catheters, steroids and GI tract colonization were not independent risk factors, but GI tract colonization preceded candidemia in 15 of 35 (43%) case patients. Conclusions. Candida spp. are an important cause of late onset sepsis in NICU patients. The incidence of candidemia might be decreased by the judicious use of treatments identified as risk factors and avoiding H2 blockers.
Article
Over a 2-year period, all surgical patients from whom Candida was isolated from intra-abdominal specimens were evaluated. All but 1 of the 49 evaluable patients had either a spontaneous perforation (57%) or a surgical opening of the gastrointestinal tract (41%). Candida caused infection in 19 patients (39%), of whom 7 had an intra-abdominal abscess and 12 peritonitis. In the other 30 patients (61%), there were no signs of infection and specific surgical or medical treatment was not required. Candida was more likely to cause infection when isolated in patients having surgery for acute pancreatitis than in those with either gastrointestinal perforations or other surgical conditions. The development of a clinical infection was significantly associated with a high initial or increasing amount of Candida in the semiquantitative culture. Surgery alone failed in 16 of 19 patients (84%), of whom 7 died and 9 recovered after combined antifungal and surgical treatment. The overall mortality and the mortality related to infections were significantly higher in the patients with intraabdominal candidal infections than in those without such infections.
Article
Approximately 5% of all hospitalized patients develop a nosocomial infection. The costs associated with such infections are estimated to be more than 1 billion dollars per year. Although bacteria are the most common etiologic agents in hospital-acquired infections, fungi are also significant nosocomial pathogens.
Article
We reviewed the clinical courses of 63 surgical patients who had experienced one or more days of fungemia, to determine the clinical setting for such infections and to define indications for systemic therapy. Fifty-one patients experienced fungemia as a late complication of intraperitoneal infection. Candida was identified as part of a polymicrobial flora in 70%. If untreated, the mortality was 83% (30 of 36). No untreated patients with fungemia for more than one day survived. Adequate therapy with amphotericin B (total dose, greater than 3 mg/kg) improved survival to 67% (ten of 15). Autopsies performed in 20 cases revealed visceral Candida microabscesses in seven, with the gastrointestinal tract (12) and intraabdominal abscess (five) as the most common sources of fungi. These data support the concept of Candida as an important participant in polymicrobial infection and recommend therapy with amphotericin B for patients with intraperitoneal infection experiencing fungemia.
Article
Various Candida species have been found increasingly in seriously ill surgical patients. This study, which evaluates the role of Candida in the pathogenesis of intraperitoneal infections, is a retrospective review of 56 episodes of intraperitoneal infection in which various Candida species were identified. All patients were on general surgical services; transplant patients were excluded. In all patients, intraperitoneal infections was confirmed at the time of operation. In 30 cases, peritonitis was the result of a spontaneous disease process - perforated viscus (25), intestinal necrosis (two), miscellaneous (three) - and in the other 26 cases, infection followed elective intraabdominal surgery. Infection was polymicrobial in 82% of the cases and the overall mortality rate was 70%. Uncontrolled sepsis was the predominant cause of death. Postmortem findings in 27 patients (of 40 deaths) showed nine cases of clinically unsuspected disseminated candidiasis, and persistent intraperitoneal Candida infection was present in eight more patients. None of the patients treated with amphotericin prior to death had residual foci of candidal infection. In 40 patients, intraperitoneal Candida was found before the onset of multiple organ failure syndromes, and survival was related to provision of systemic antifungal therapy before blood cultures became positive. Five of six patients treated prior to the development of positive blood cultures survived, whereas only nine of 27 untreated patients survived. If therapy was withheld until blood cultures became positive, only two out of six patients survived. Low-dose therapy consisting of 0.3 to 0.5 mg amphotericin B/kg daily for 7 days was equally effective as more prolonged treatment. We conclude that when Candida is identified as part of the intraperitoneal flora at operation for intraperitoneal infection, it should be treated with low-dose amphotericin B. Treatment should not be delayed until blood cultures become positive. Therapy should be monitored with repetitive cultures of multiple sites and with fundoscopy. No relapse occurred in patients so treated.
Article
The authors determined the role of Candida colonization in the development of subsequent infection in critically ill patients. A 6-month prospective cohort study was given to patients admitted to the surgical and neonatal intensive care units in a 1600-bed university medical center. Patients having predetermined criteria for significant Candida colonization revealed by routine microbiologic surveillance cultures at different body sites were eligible for the study. Risk factors for Candida infection were recorded. A Candida colonization index was determined daily as the ratio of the number of distinct body sites (dbs) colonized with identical strains over the total number of dbs tested; a mean of 5.3 dbs per patient was obtained. All isolates (n = 322) sequentially recovered were characterized by genotyping using contour-clamped homogeneous electrical field gel electrophoresis that allowed strain delineation among Candida species. Twenty-nine patients met the criteria for inclusion; all were at high risk for Candida infection; 11 patients (38%) developed severe infections (8 candidemia); the remaining 18 patients were heavily colonized, but never required intravenous antifungal therapy. Among the potential risk factors for candida infection, three discriminated the colonized from the infected patients--i.e., length of previous antibiotic therapy (p < 0.02), severity of illness assessed by APACHE II score (p < 0.01), and the intensity of Candida spp colonization (p < 0.01). By logistic regression analysis, the latter two who were the independent factors that predicted subsequent candidal infection. Candida colonization always preceded infection with genotypically identical Candida spp strain. The proposed colonization indexes reached threshold values a mean of 6 days before Candida infection and demonstrated high positive predictive values (66 to 100%). The intensity of Candida colonization assessed by systematic screening helps predicting subsequent infections with identical strains in critically ill patients. Accurately identifying high-risk patients with Candida colonization offers opportunity for intervention strategies.
Article
To identify pathogens causing nosocomial fungal infections and the secular trend in their incidence in US hospitals, data from the National Nosocomial Infections Surveillance System, 1980-1990, were analyzed. During that period, 30,477 fungal infections were reported. The rate rose from 2.0 to 3.8 infections/1000 discharges. The highest number of nosocomial fungal infections/1000 discharges was reported from the burn/trauma service (16.1). Candida albicans was the most frequently isolated fungal pathogen (59.7%), followed by other Candida species (18.6%). The rate increased at all four major anatomic sites of infection. Patients with bloodstream infections who had a central intravascular catheter were more likely to have a fungal pathogen isolated than were other patients with bloodstream infection (relative risk = 3.2; P < .001): 29% of fungemia patients and 17% of patients with bloodstream infection due to other pathogens died during hospitalization (P < .001). Fungi are emerging as important nosocomial pathogens and control efforts should target fungal infections, especially fungemia.
Article
This paper briefly reviews the current knowledge of the epidemiology and modes of transmission of nosocomial fungal infections and some of the therapeutic options for treating these diseases. In the mid-1980s, many institutions reported that fungi were common pathogens in nosocomial infections. Most, if not all, hospitals care for patients at risk for nosocomial fungal infections. The proportion in all nosocomial infections reportedly caused by Candida spp. increased from 2% in 1980 to 5% in 1986 to 1989. Numerous studies have identified common risk factors for acquiring these infections, most of which are very common among hospitalized patients; some factors act primarily by inducing immunosuppression (e.g., corticosteroids, chemotherapy, malnutrition, malignancy, and neutropenia), while others primarily provide a route of infection (e.g., extensive burns, indwelling catheter), and some act in combination. Non-albicans Candida spp., including fluconazole-resistant C. krusei and Torulopsis (C.) glabrata, have become more common pathogens. Newer molecular typing techniques can assist in the determination of a common source of infection caused by several fungal pathogens. Continued epidemiologic and laboratory research is needed to better characterize these pathogens and allow for improved diagnostic and therapeutic strategies.
Article
The incidence of systemic Candida infections in patients requiring intensive care has increased substantially in recent years as a result of a combination of factors. More patients with severe underlying disease or immunosuppression from anti-neoplastic or anti-rejection chemotherapy and at risk from fungal infection are now admitted to the ICU. Improvements in supportive medical and surgical care have led to many patients who would previously have died as a result of trauma or disease surviving to receive intensive care. Moreover, some therapeutic interventions used in the ICU, most notably broad-spectrum antibiotics and intravascular catheters, are also associated with increased risks of candidiasis. Systemic Candida infections are associated with a high morbidity and mortality, but remain difficult to diagnose and ICU staff need to be acutely aware of this often insidious pathogen. A number of studies have identified risk factors for systemic Candida infection which may be used to identify those at highest risk. Such patients may be potential candidates for early, presumptive therapy. Here we review the epidemiology, pathogenesis, morbidity and mortality of systemic Candida infections in the ICU setting, and examine predisposing risk factors. Antifungal treatment, including the use of amphotericin B, flucytosine and fluconazole, and the roles of early presumptive therapy and prophylaxis, is also reviewed.
Article
To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. Randomized, prospective, double-blind, placebo-controlled study. Two university-affiliated hospitals in Switzerland. Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.
Article
An international program of surveillance of bloodstream infections (BSI) in the United States, Canada, and Latin America detected 306 episodes of candidemia in 34 medical centers (22 in the United States, 6 in Canada, and 6 in Latin America) in 1997 and 328 episodes in 34 medical centers (22 in the United States, 5 in Canada, and 7 in Latin America) in 1998. Of the 634 BSI, 54.3% were due to Candida albicans, 16.4% were due to C. glabrata, 14.9% were due to C. parapsilosis, 8.2% were due to C. tropicalis, 1.6% were due to C. krusei, and 4.6% were due to other Candida spp. The percentage of BSI due to C. albicans decreased very slightly in the United States between 1997 and 1998 (56.2 to 54.4%; P = 0.68) and increased in both Canada (52.6 to 70.1%; P = 0.05) and Latin America (40.5 to 44. 6%; P = 0.67). C. glabrata was the second most common species observed overall, and the percentage of BSI due to C. glabrata increased in all three geographic areas between 1997 and 1998. C. parapsilosis was the third most prevalent BSI isolate in both Canada and Latin America, accounting for 7.0 and 18.5% of BSI, respectively. Resistance to fluconazole (MIC, >/=64 microgram/ml) and itraconazole (MIC, >/=1.0 microgram/ml) was observed infrequently in both 1997 (2.3 and 8.5%, respectively) and 1998 (1.5 and 7.6%, respectively). Among the different species of Candida, resistance to fluconazole and itraconazole was observed in C. glabrata and C. krusei, whereas isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to both fluconazole (98.9 to 100% susceptible) and itraconazole (96.4 to 100% susceptible). Isolates from Canada and Latin America were generally more susceptible to both triazoles than U.S. isolates were. Continued surveillance appears necessary to detect these important changes.
Article
Candida species are important nosocomial pathogens in neonatal intensive care unit (NICU) patients. A prospective cohort study was performed in six geographically diverse NICUs from 1993 to 1995 to determine the incidence of and risk factors for candidemia, including the role of gastrointestinal (GI) tract colonization. Study procedures included rectal swabs to detect fungal colonization and active surveillance to identify risk factors for candidemia. Candida strains obtained from the GI tract and blood were analyzed by pulsed field gel electrophoresis to determine whether colonizing strains caused candidemia. In all, 2,847 infants were enrolled and 35 (1.2%) developed candidemia (12.3 cases per 1,000 patient discharges or 0.63 case per 1,000 catheter days) including 23 of 421 (5.5%) babies < or =1,000 g. After adjusting for birth weight and abdominal surgery, forward multivariate logistic regression analysis demonstrated significant risk factors, including gestational age <32 weeks, 5-min Apgar <5; shock, disseminated intravascular coagulopathy, prior use of intralipid, parenteral nutrition, central venous catheters, H2 blockers, intubation or length of stay > 7 days before candidemia (P < 0.05). Catheters, steroids and GI tract colonization were not independent risk factors, but GI tract colonization preceded candidemia in 15 of 35 (43%) case patients. Candida spp. are an important cause of late onset sepsis in NICU patients. The incidence of candidemia might be decreased by the judicious use of treatments identified as risk factors and avoiding H2 blockers.
Article
To evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. Invasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. The authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. The primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. Enteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.
Article
The incidence of invasive fungal infections, particularly invasive candidiasis, after liver transplantation is strongly influenced by surgical factors and technical complexity of the surgery. We assessed the temporal trends in invasive fungal infections in the context of evolution in liver transplantation practices, technical developments, and other risk factors. Demographic and clinical characteristics of the patients, transplantation-related variables, and rates of infection were longitudinally analyzed over the last 10 years in 190 consecutive liver transplant recipients at our institution. Trends for categorical data were evaluated using the Cochran-Armitage trend test and for continuous variables using analysis of variance with linear contrast. A decrease in the length of operation (P=0.03), intraoperative transfusion requirements (P=0.0001), cold ischemic time (P<0.0001), use of roux-en-Y biliary anastomosis (P=0.0015), rate of biopsy proven rejection (P<0.0001), and retransplantation (P=0.056) was documented over the successive years. A significant decline in Child-Pugh score (P=0.02) and in the proportion of patients transplanted as UNOS 2a occurred (P=0.0001). Although the incidence of cytomegalovirus infection remained unchanged, a significant increase in the frequency of primary cytomegalovirus infection (P=0.045), and a decrease in cytomegalovirus disease (P=0.0006) was documented. Over the same time period, a significant decrease in the incidence of invasive candidiasis (P=0.015), and an insignificant increase in the rate of invasive aspergillosis (P=0.20) occurred. Notable technical developments in liver transplantation practices and risk profiles of patients have occurred over the decade. These variables may have a role in influencing the evolving trends in invasive fungal infections in liver transplant recipients.
Article
Sepsis represents a substantial health care burden, and there is limited epidemiologic information about the demography of sepsis or about the temporal changes in its incidence and outcome. We investigated the epidemiology of sepsis in the United States, with specific examination of race and sex, causative organisms, the disposition of patients, and the incidence and outcome. We analyzed the occurrence of sepsis from 1979 through 2000 using a nationally representative sample of all nonfederal acute care hospitals in the United States. Data on new cases were obtained from hospital discharge records coded according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Review of discharge data on approximately 750 million hospitalizations in the United States over the 22-year period identified 10,319,418 cases of sepsis. Sepsis was more common among men than among women (mean annual relative risk, 1.28 [95 percent confidence interval, 1.24 to 1.32]) and among nonwhite persons than among white persons (mean annual relative risk, 1.90 [95 percent confidence interval, 1.81 to 2.00]). Between 1979 and 2000, there was an annualized increase in the incidence of sepsis of 8.7 percent, from about 164,000 cases (82.7 per 100,000 population) to nearly 660,000 cases (240.4 per 100,000 population). The rate of sepsis due to fungal organisms increased by 207 percent, with gram-positive bacteria becoming the predominant pathogens after 1987. The total in-hospital mortality rate fell from 27.8 percent during the period from 1979 through 1984 to 17.9 percent during the period from 1995 through 2000, yet the total number of deaths continued to increase. Mortality was highest among black men. Organ failure contributed cumulatively to mortality, with temporal improvements in survival among patients with fewer than three failing organs. The average length of the hospital stay decreased, and the rate of discharge to nonacute care medical facilities increased. The incidence of sepsis and the number of sepsis-related deaths are increasing, although the overall mortality rate among patients with sepsis is declining. There are also disparities among races and between men and women in the incidence of sepsis. Gram-positive bacteria and fungal organisms are increasingly common causes of sepsis.
Article
To assess the efficacy of a preemptive antifungal therapy in preventing proven candidiasis in critically ill surgical patients. Before/after intervention study, with 2-yr prospective and 2-yr historical control cohorts. Surgical intensive care unit (SICU) in a university-affiliated hospital. Nine hundred and thirty-three patients, 478 in the prospective group and 455 in the control group, with SICU stay > or =5 days. During the prospective period, systematic mycological screening was performed on all patients admitted to the SICU, immediately at admittance and then weekly until discharge. A corrected colonization index was used to assess intensity of Candida mucosal colonization. Patients with corrected colonization index > or =0.4 received early preemptive antifungal therapy (fluconazole intravenously: loading dose 800 mg, then 400 mg/day for 2 wks). End points of this study were the frequency of proven candidiasis, especially SICU-acquired candidiasis. During the retrospective period, 32 patients of 455 (7%) presented with proven candidiasis: 22 (4.8%) were imported and 10 (2.2%) were SICU-acquired cases. During the prospective period, 96 patients with corrected colonization index > or =0.4 of 478 received preemptive antifungal treatment and only 18 cases (3.8%) of proven candidiasis were diagnosed; all were imported infections. Candida infections occurred more frequently in the control cohort (7% vs. 3.8%; p = .03). Incidence of SICU-acquired proven candidiasis significantly decreased from 2.2% to 0% (p < .001, Fisher test). Incidence of proven imported candidiasis remained unchanged (4.8% vs. 3.8%; p = .42). No emergence of azole-resistant Candida species (especially Candida glabrata, Candida krusei) was noted during the prospective period. Targeted preemptive strategy may efficiently prevent acquisition of proven candidiasis in SICU patients. Further studies are being performed to assess cost-effectiveness of this strategy and its impact on selection of azole-resistant Candida strains on a long-term basis.
Article
Background: Invasive fungal infections, important causes of morbidity and mortality in critically ill patients, may be preventable with the prophylactic administration of antifungal agents. Objectives: This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005), and EMBASE (1980 to week 36, 2005). We also handsearched reference lists, abstracts of conference proceedings and scientific meetings (1998 to 2004), and contacted authors of included studies and pharmaceutical manufacturers. Selection criteria: We included randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen in non-neutropenic critically ill adult patients. Data collection and analysis: Two authors independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. We resolved differences by discussion. We synthesized data using the random effects model and expressed results as relative risk with 95% confidence intervals. Main results: We included 12 unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a nonabsorbable agent) involving 1606 randomized patients. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by about 25% (relative risk 0.76, 95% confidence interval 0.59 to 0.97) and invasive fungal infections by about 50% (relative risk 0.46, 95% confidence interval 0.31 to 0.68). We identified no significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or C. krusei, although the confidence intervals of the summary effect measures were wide. Adverse effects were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. Authors' conclusions: Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one half and total mortality by one quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.
Article
Despite the widespread use of antifungals for prophylaxis, Candida bloodstream infection (BSI) remains the most frequent life-threatening fungal disease. From an analysis of multi-institutional surveys of Candida BSIs performed in Europe, including the large prospective survey by the European Confederation of Medical Mycology (2089 episodes from seven countries), a limited role of species with decreased susceptibility to azoles in causing BSIs and a low proportion of antifungal resistance was evident. Large prospective epidemiological surveys using common databases are needed to monitor trends in incidence and changes in species distribution, to identify new at-risk patients and to evaluate the impact of the introduction into the market of new antifungal agents.
The epidemiology of sepsis in the United States from 1979 through
  • Martin Gs Dm Mannino
  • S Eaton
Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003 Apr 17; 348 (16): 1546-54
Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey
  • Hm Blumberg
  • Wr Jarvis
  • Jm Soucie
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